SARS-CoV-2 beim Menschen
Berliner und Münchener Tierärztliche Wochenschrift 134, 1-13
© Schlütersche Fachmedien GmbH. 2021
The novel coronavirus SARS-CoV-2 became pandemic at the beginning of 2020, and caused about 80 million cases and more than 1.8 million deaths by the end of the year. As its relatives MERS- and SARS-CoV, but in contrast to the four human coronaviruses circulating worldwide, SARS-CoV-2 in a sizeable fraction of cases leads to a severe and potentially life-threatening disease, called COVID-19. Since in addition this virus is very contagious, particularly prior to onset or in absence of symptoms, and pre-existing immunity appears to be largely absent or at least of very little relevance, it is spreading rapidly in the population. A hallmark of COVID-19 is an at least partially detrimental immune response that not only can lead to serious lung damage, but may also damage organs outside the respiratory tract such as the heart and kidneys. This review summarizes current knowledge about the virus and the disease it causes, and outlines open questions in the different research fields.
Das neuartige Coronavirus SARS-CoV-2 wurde Anfang 2020 zur Pandemie und verursachte bis Ende des Jahres etwa 80 Millionen Fälle und mehr als 1,8 Millionen Todesfälle. Wie seine Verwandten MERS- und SARS-CoV, aber im Gegensatz zu den weltweit zirkulierenden vier menschlichen Coronaviren, führt SARS-CoV-2 in einem beträchtlichen Teil der Fälle zu einer schweren und potenziell lebensbedrohlichen Krankheit: COVID-19. Da dieses Virus zudem schon vor Ausbruch bzw. auch ohne Symptome sehr ansteckend ist und möglicherweise vorexistierende Immunität sehr begrenzt zu sein scheint, breitet es sich in der Bevölkerung rasch aus. Ein Kennzeichen von COVID-19 ist eine zumindest teilweise fehlgeleitete Immunantwort, die nicht nur zu schweren Lungenschäden führen, sondern auch Organe außerhalb des Respirationstraktes wie Herz und Nieren schädigen kann. Dieser Übersichtsartikel fasst den aktuellen Wissensstand über das Virus und die von ihm verursachte Krankheit zusammen und skizziert offene Fragen in verschiedenen biomedizinischen Forschungsbereichen.
The first human Coronaviruses (hCoVs) have been isolated some 50 years ago from individuals suffering from mild respiratory infections. Four such “common cold” coronaviruses are known to circulate worldwide in humans, namely hCoV-NL63, -HKU1, -229E, and -OC43 (Almeida and Tyrrell 1967, Fehr and Perlman 2015, Masters and Perlman 2013). In stark contrast, two zoonotic coronaviruses infecting humans and capable of spreading in the human population have been described to cause severe to life-threatening diseases: severe acute respiratory syndrome coronavirus (SARS-CoV), first emerging in 2002 and rapidly spreading to several countries around the globe (covered in detail by A. Osterhaus in this volume); and middle-east respiratory syndrome coronavirus (MERS-CoV), first described in 2012 (covered in detail by Asisa Volz in this volume). While circulation of SARS-CoV could be successfully contained by globally implemented public health measures, cases of MERS-CoV infection are still regularly reported, mainly on the Arabian peninsula (World Health Organization 2020a).
In December 2019, cases of severe pneumonia of unknown – but likely infectious – etiology in the city of Wuhan, China, have been reported to the WHO (World Health Organization 2020c), which were shortly after linked to a newly isolated coronavirus, first termed 2019-nCoV (World Health Organization 2020b). Due to its high similarity to SARS-CoV, the virus was later renamed SARS-CoV-2. However, as highlighted in other articles within this volume, coronaviruses have been identified and isolated from a large range of other mammalian species, particularly bats. In fact, RaTG13, a coronavirus found in a horseshoe bat in Yunnan province, China, exhibits an even higher degree of similarity than SARS-CoV to the newly emerged SARS-CoV-2 with approximately 96% of sequence identity at the nucleotide level throughout most genomic regions. It therefore appears likely that SARS-CoV-2 originated from a zoonotic event, either directly from bat or via an intermediate host (Andersen et al. 2020; Boni et al. 2020). Backing this hypothesis, the virus’ potential to readily cross species barriers was demonstrated by documented cases of SARS-CoV-2 transmission from humans to household animals (Shi et al. 2020; Sit et al. 2020) and from humans to farmed mink and back to humans (Oude Munnink et al. 2020). From lab experiments, it is known that particularly changes in the spike protein on the surface of the virions can lead to interspecies adaption in coronaviruses (Baric et al. 1997).
While the exact origin of SARS-CoV-2 still is under investigation, its impact on the human population has been dramatic. Since its first outbreak in Wuhan, it has spread with remarkable pace around the world, causing upwards of 80 million reported cases by the end of 2020, with more than 1.8 million deaths (World Health Organization 2021), and still raging. With SARS-CoV-2 and the associated coronavirus disease 2019 (COVID-19), human society thus faces a pandemic unbeknownst to living generations, with a broad spectrum of challenges for all disciplines of science. This article covers some of the key questions from the various branches of biomedical research.
Molecular biology of SARS-CoV-2 infection
Decades of research into the other coronaviruses have set the stage for fast progress in investigating SARS-CoV-2. As the general organization of the genes, detailed below, is conserved among all coronaviruses, SARS-CoV-2 was rapidly deciphered and viral protein coding genes were quickly defined. Furthermore, most aspects of the viral molecular lifecycle are shared with other coronaviruses (comprehensively reviewed in (V’Kovski et al. 2020)). As a plus-strand RNA virus, its genome constitutes a messenger RNA for the direct translation of viral proteins. Released from incoming virions into the cytosol right after cell entry, the viral genome serves as the message to produce viral proteins, which are translated as two long polypeptide precursors pp1a and pp1ab. The two polyproteins are then proteolytically cleaved by the viral cysteine proteases, non-structural protein nsp3 (PLpro) and nsp5 (3CLpro), giving rise to the 16 nsps of the virus. These provide a multitude of enzymatic activities required for viral genome replication and the modulation of host cellular processes. One essential enzymatic function not present in the human genome is the RNA-dependent RNA polymerase (RdRp), comprising nsp12, nsp8 and nsp7, which is also the target of the direct acting antiviral (DAA) remdesivir (Sheahan et al. 2020). The RdRP then, through negative-strand intermediates, generates copies of the full-length genomic RNA as well as eight species of subgenomic mRNAs (sgmRNAs). Those sgmRNAs code for structural proteins including nucleocapsid (N), spike (S), envelope (E) and membrane (M), as well as numerous auxiliary proteins. From other coronaviruses, in particular SARS-CoV, it is known that some of them antagonize host cellular antiviral defense pathways, most prominently the induction of and signaling by type I and III interferons (Park and Iwasaki 2020). Also, SARS-CoV-2 has been shown to encode an ample variety of activities targeting the host interferon and cytokine system (Hayn et al. 2020, Lei et al. 2020), believed to play a central role in dysregulating the immune response to infection and thereby crucially contributing to the development of COVID-19 (Acharya et al. 2020, Mathew et al. 2020, McKechnie and Blish 2020).
From the structural proteins together with genomic RNA, new virions are formed by budding into membranous structures at the interface between the endoplasmic reticulum (ER) and the Golgi apparatus, likely representing the ER-Golgi-intermediate compartment (ERGIC), coherent with previous reports on other coronaviruses (Cortese et al. 2020, Fehr and Perlman 2015, Masters and Perlman 2013). Offspring virus particles are then released through exocytic processes, not strictly requiring cell lysis.
Released viral particles will then infect neighboring cells. Again owing to the close similarity to related viruses, including SARS-CoV, angiotensin converting enzyme 2 (ACE2), which plays a major role in regulating electrolyte and fluid balance as well as blood pressure (Verano-Braga et al. 2020), was readily identified as the major receptor for cell entry (Hoffmann et al. 2020). Alternative entry receptors, such as CD147 or NRP1, are currently under discussion (Cantuti-Castelvetri et al. 2020, Daly et al. 2020, Shilts and Wright 2020, Wang et al. 2020a). It was further confirmed that the SARS-CoV-2 spike protein requires proteolytic processing (“priming”) to mediate entry, and that this priming can be efficiently mediated by the cellular membrane-bound TMPRSS2 protease (Hoffmann et al. 2020). TMPRSS2 as well as further cellular proteases shown to play alternative or redundant roles, including furin and cathepsin L, can be pharmacologically targeted to prevent infection (Hoffmann et al. 2020, Pislar et al. 2020, Shang et al. 2020).
Transmission and epidemiology of SARS-CoV-2
In contrast to many animal coronaviruses, all known hCoVs primarily infect and replicate in cells of the respiratory tract, and SARS-CoV-2 is no exception in this regard (Fehr and Perlman 2015, Masters and Perlman 2013, Salzberger et al. 2020). In contrast to SARS-CoV, mostly replicating in epithelial cells of the lower respiratory tract, SARS-CoV-2 was found to infect and efficiently replicate also in cells of the upper respiratory tract, with nasopharyngeal and oropharyngeal swabs but also saliva containing high amounts of viral RNA and infectious virus (Cevik et al. 2020a, Wolfel et al. 2020, Wyllie et al. 2020). As a consequence, SARS-CoV-2 can easily transmit upon coughing, sneezing, singing and even talking. These activities produce a spray of droplets ranging from visible, large droplets, which will fall to the ground relatively quickly compared to microscopic (< 100 µM) (Prather et al. 2020) droplet nuclei lingering in the air as aerosols (Fennelly 2020, Klompas et al. 2020, van Doremalen et al. 2020). While transmission by larger droplets appears more prevalent, long distance transmission by aerosols may, at least in part, explain so-called “superspreading events”, in which a small number of index patients, or even only a single infected person, transmit the virus to large numbers of people in the same confined space (Cevik et al. 2020a), for example in large open-plan offices (Park et al. 2020b), festivities (Ghinai et al. 2020), churches (James et al. 2020), meat processing facilities (Guenther et al. 2020) or choirs (Hamner et al. 2020). Similar to SARS-CoV, but different from most seasonal respiratory viral infections, the higher propensity of SARS-CoV-2 to transmit via such one-to-many “superspreading events” needs to be taken into account for epidemiological modelling. The number of secondary cases caused by single patients is generally very low, between zero and one for most patients, but follows a negative binomial distribution with a very long tail, corresponding to an average R0 between 2 and 3 with a small (much less than 1) dispersion parameter (Adam et al. 2020, Althouse et al. 2020, Kupferschmidt 2020, Li et al. 2020a, Liu et al. 2020b, Park et al. 2020a).
Another feature of SARS-CoV-2 transmission is pre-symptomatic contagiousness, and possibly transmission by infectees who remain fully asymptomatic. While the extent of the contribution of truly asymptomatic carriers to the overall epidemiology of SARS-CoV-2 is still debated, transmission one to two days prior to the onset of symptoms likely plays a decisive role in rapid community spread (Cevik et al. 2020a, Kasper et al. 2020). In general, transmissibility is highest around the onset of symptoms and quickly declining thereafter (Cevik et al. 2020b).
Taking those basic epidemiological characteristics into account, policy responses at the beginning of the pandemic early on prohibited large gatherings and especially indoor events with large numbers of attendees, and in a second step, many countries promoted the use of face masks to curb virus spread (Flaxman et al. 2020). By and large, these public health measures were shown to be actually effective (Chu et al. 2020, Dehning et al. 2020). However, epidemiological analyses are still ongoing, as the situation is highly complex and differs between regions, countries and continents. In general, human respiratory viruses and in particular the endemic hCoVs exhibit clear seasonal profiles (Moriyama et al. 2020). In fact, Europe experienced a low-incidence situation throughout summer, but suffered from steeply increasing case numbers from September/October on, reaching multiples of the numbers recorded in spring (Cacciapaglia et al. 2020, European Centre for Disease Prevention and Control 2020, Looi 2020).
The use of high-throughput RNA sequencing to determine the entire sequence of patient isolates, although varying between countries, has identified a myriad of sequence variants, which are deposited and available through database platforms such as NextStrain (Hadfield et al. 2018). Phylogenetic analyses of viral sequences enable close tracking of the mutational course of the virus. This not only permits the precise reconstruction of transmission chains and epidemiologic events (Popa et al. 2020), but also allows for worldwide monitoring of the genomic landscape of SARS-CoV-2 and the identification of mutations that got fixed in the viral genome. Mutations within the S protein of circulating viruses are particularly in focus, as it is both the major determinant for efficient cell entry and the major antigen for neutralizing antibody responses. Also mutations in other parts of the genome might confer increased virulence. Of note, coronaviruses generally have relatively low mutation rates as they uniquely bear a proofreading replication mechanism, likely due to their genomes being amongst the largest (~30,000 bases) of all RNA viruses (Fehr and Perlman 2015, Masters and Perlman 2013).
An early spike protein mutation, D614G, emerged within the first weeks of the pandemic and quickly took over (Korber et al. 2020). In fact, it could be demonstrated that the D614G variant shifts the S protein conformation towards higher ACE2-binding and fusogenicity, leading to increased infectivity of the virus in vitro (Korber et al. 2020, Yurkovetskiy et al. 2020). Recently, it was confirmed that also in vivo transmissibility in animal models was significantly enhanced in the D614G variant, however, pathogenicity was not (Hou et al. 2020a). In December 2020, a new variant (B1.1.7) bearing several mutations in the S protein was identified in the United Kingdom, which was spreading rapidly, again indicating significantly higher transmissibility (Davies et al. 2020).
Clinical characteristics of COVID-19
Respiratory viruses are very common. Rhinoviruses, adenoviruses, respiratory syncytial viruses and of course influenza- and coronaviruses, cause a range of illnesses, including the very frequent common cold. SARS-CoV-2 was initially described to cause severe viral pneumonia, resembling the clinical picture of SARS and MERS, displaying typical ground-glass-opacities in chest radiography and leading to acute respiratory distress syndrome (ARDS) in a sizeable proportion of patients (Huang et al. 2020). As sensitive and specific molecular testing became more readily available (Corman et al. 2020), it was found that SARS-CoV-2 infection in fact presents a broad outcome, from asymptomatic to life-threatening (Docherty et al. 2020). Whereas initially up to four out of five infections were thought to occur with no or very mild symptoms (Keeley et al. 2020), this number dropped to currently about one in six (Cevik et al. 2021). Approximately 20% of cases require hospitalization (Kasper et al. 2020, Pollan et al. 2020), 5–10% are admitted to intensive care (Phua et al. 2020) and 0.1%–2% are dying. This “infection fatality rate” shows substantial variation between different reports, which could be due to underlying, e.g. geographical or social, differences (Levin et al. 2020, O’Driscoll et al. 2020, Pastor-Barriuso et al, 2020, Stadlbauer et al. 2020). Severity of the disease, and in particular mortality increases significantly with male sex and drastically with the infectee’s age, reaching infection fatality rates of up to 10% in those aged above 80 (O’Driscoll 2020). Besides sex and age, pre-existing conditions strongly affect the risk of severe COVD-19, including hypertension, cardiovascular disease, COPD and diabetes (Cevik et al. 2020a, Cevik et al. 2020b, Liang et al. 2020, Trump et al. 2020, Williamson et al. 2020). Apart from severe acute disease and death, even for less severe course of COVID-19, long-term complications such as fatigue, impaired physical fitness, or mental health probles, are receiving increasing attention (Carfi et al. 2020, Huang et al. 2021, Mitrani et al. 2020, Nature Medicine Editorial 2020). Such long-term effects are also known to occur following influenza infections (Wang et al. 2020b), however causes and virus-specific aspects remain to be elucidated.
Among the most frequently reported symptoms of SARS-CoV-2 infection are headache, non-productive cough and a unique impairment of the sense of smell and taste (Kasper et al. 2020, Makaronidis et al. 2020). In contrast to initial reports, which were somewhat biased towards hospitalized cases, fever is reported in a significantly smaller fraction of cases (Kasper et al. 2020). In more severe courses of COVID-19, these initial, flu-like symptoms are then followed by generalized weakness, chest pressure or pain and a shortness of breath (Hall et al. 2020). Although classical signs of atypical pneumonia can already be appreciated in chest radiography, the general condition of the patient may remain stable, with acute pulmonary symptoms going along with a rapid decline in oxygen saturation only setting in with significant delay (Herrmann et al. 2020, Rubin et al. 2020, Tobin et al. 2020). A sizeable fraction of patients requiring intensive care deteriorate significantly developing ARDS and requiring mechanical ventilation or even extracorporeal membrane oxygenation (ECMO), which is the only life-saving measure left in the most critical cases (Barbaro et al. 2020). Still, respiratory failure due to ARDS is the leading cause of COVID-19 related deaths, accounting for approximately 70% of fatal cases (Zhang et al. 2020a).
An increasing body of literature further suggests other organs in the human body to be affected. In particular the loss of smell and taste was speculated to be due to direct viral infection of cells of the olfactory system (Bilinska and Butowt 2020, Butowt and von Bartheld 2020, Meinhardt et al. 2020). Further reported extra-pulmonary manifestations of COVID-19 include (but are not limited to) diarrhea, gastrointestinal and liver injury (Lamers et al. 2020, Zhong et al. 2020), myocarditis (Puntmann et al. 2020), renal failure (Gabarre et al. 2020) as well as severe endothelial damage and increased blood clotting (Perico et al. 2021). Whether those symptoms are caused by direct viral infections is still under investigation. ACE2, the main entry receptor for SARS-CoV-2, is expressed on cells of various organs (Ziegler et al. 2020). Indeed, in vitro infections were efficient on a range of models including cardiomyocytes, brain organoids, pancreatic cells, gut and liver organoids to name a few (Yang et al. 2020a). However, presence of infectious viral particles in the bloodstream would be assumed to be required for infection of distal organs, but is only scarcely detected (Walsh et al. 2020).
COVID-19 pathogenesis and treatment options
The pathomechanisms underlying this very broad spectrum of symptoms are only begun to be understood. An emerging general view is that the disease proceeds in two phases (Li et al. 2020b, Tay et al. 2020). In the first phase, the virus infects and replicates in epithelial cells of the upper respiratory tract. It then spreads and descends until it reaches cells in the lung, likely alveolar epithelial cells. During this phase, viral infection induces innate immune responses, recruiting macrophages and monocytes, but also cytotoxic cells to the sites of infection. It is likely that in the majority of patients suffering no or only mild symptoms, this regular immune response is sufficient to effectively control the virus.
However, in moderate to critical courses of the disease, a second phase with potentially life-threatening consequences initiates. The currently prevalent hypothesis focuses on the hyperactivation of immune cells and a massive secretion of cytokines, sometimes termed “cytokine storm” (Li et al. 2020b, Mangalmurti and Hunter 2020, Moore and June 2020, Tay et al. 2020). Albeit not fully understood, it appears likely that following infection, the cellular response is shifted away from antiviral interferons towards pro-inflammatory cytokine secretion (Acharya et al. 2020, Galani et al. 2021, Neufeldt et al. 2020).
Broadly speaking, the research on the causes of severe COVID-19 can be divided in two areas. First, there is the question of where and how does this detrimental response to the infection initiates. Second, factors that contain or amplify and worsen the outcome shall be identified.
To answer the first question, experiments are conducted in a range of model systems and combined with data from patient samples. An important limitation for the latter is that due to the lag time from infection to symptom onset and hospitalization, early stages of the infection cannot be monitored.
Initial studies in cell culture showed an induction of pro-inflammatory genes in virus-infected epithelial cells (Blanco-Melo 2020), however, as for interferon genes, only in small subsets of cells (Fiege et al. 2020, Wyler et al. 2020). Data from bronchoalveolar lavages (Liao et al. 2020), ex vivo infected human lung tissue (Hönzke et al. 2020) or Syrian hamsters (Nouailles et al. 2020) indicate that, at least in the lower airways, infection of epithelial cells is neither particularly efficient, likely also due to low levels of ACE2 expression (Hönzke et al. 2020, Hou et al. 2020b), nor elicits a strong transcriptional response. However, these studies support an important role for macrophages in triggering a potentially excessive pro-inflammatory response. Along these lines, macrophages in samples from upper airways showed higher expression of pro-inflammatory cytokines in patients with critical compared to moderate COVID-19 (Chua et al. 2020). Infiltration of lung alveolae by myeloid cells, particularly neutrophils (Potey et al. 2019), along with interstitial liquid, then leads to a significant impairment of the respiratory capacity and, hence, ARDS. The strong increase of inflammatory cytokines such as interleukin 6 or tumor necrosis factor (TNF) may constitute an important factor for observed manifestations at distal sites, such as damage to blood vessels or the kidney and increased blood clotting (Acharya et al. 2020, Mangalmurti and Hunter 2020, Perico et al. 2021, Tay et al. 2020).
A range of aspects potentially modulating the grade of the disease are currently investigated. In one study, impaired interferon type I response was observed in severe and critical COVID-19 patients (Hadjadj et al. 2020). However, other reports presented different conclusions (Lee and Shin 2020), and a large clinical trial did not find a positive effect for the proposed treatment of COVID-19 using interferons (Consortium et al. 2020). Still, this topic will likely remain a focus, since loss-of-function polymorphisms of interferon inducing pathways and autoantibodies against type I interferons were found to be important risk factors (Bastard et al. 2020, Zhang et al. 2020b). With regard to the humoral immune response, both specific temporal profiles (Lucas et al. 2020, Zohar et al. 2020) and sugar modifications of antibodies (Chakraborty et al. 2021, Larsen et al. 2020) have been connected to disease severity. Furthermore, genome-wide association studies identified specific alleles of several genes to be significantly linked to the course of the disease (Pairo-Castineira et al. 2020, Severe Covid et al. 2020). Finally, the role of immune cells in the peripheral blood is under intense scrutiny. Different subtypes were found to be deregulated, which could also serve as prognostic markers (Chua et al. 2020, Mathew et al. 2020, Schulte-Schrepping et al. 2020, Silvin et al. 2020).
Consistent with the notion of an important role of pro-inflammatory signals in COVID-19, the immune modulatory corticosteroid dexamethasone was shown to benefit patients (Stratton et al. 2020) suffering from severe/critical disease, as were – to certain extents – the JAK/STAT inhibitor baricitinib (Kalil et al. 2020) and the IL-6 receptor antagonist tocilizumab (RECOVERY Collaborative Group et al. 2021). In further support of the notion of immune- rather than direct virus-driven pathology, compounds directly interfering with viral replication, in particular the initially promising viral RdRP inhibitor remdesivir, were tested in several trials, but eventually provided only weak support for regular use (Beigel et al. 2020, Consortium et al. 2020). Virus-directed therapeutic antibodies however showed more promising results in that they were able to reduce viral load (Chen et al. 2021, Weinreich et al. 2021).
Immunity to SARS-CoV-2
For the four common cold hCoVs, current knowledge indicates that immunity is often partial and might not last longer than several months to a few years (Edridge et al. 2020). However, due to their widespread circulation, through recurrent infections antibody serum levels can remain elevated (Edridge et al. 2020). It has been proposed that a certain degree of immunity may be cross-protective between the different endemic hCoVs and in fact, a small percentage of SARS-CoV-2-naïve sera contained anti-hCoV-IgG capable of neutralizing SARS-CoV-2 (Ng et al. 2020). Along these lines, a certain cross-reactivity was also shown on the level of memory B cells (Sokal et al. 2021). A stronger and putatively longer lasting effect was seen in T-cell responses, where circulating T-lymphocytes specific to epitopes of endemic hCoVs proved to be cross-reactive to epitopes of SARS-CoV-2 (Braun et al. 2020, Le Bert et al. 2020, Mateus et al. 2020). Of note, these studies have shown cross-reactivity, however, it remains to be investigated if these responses would be protective (de Vries 2020), and even if so, it may not have substantial impact on the current epidemiological understanding of the pandemic (Lipsitch et al. 2020).
Whereas pre-existing immunity, as described above, likely has a very limited impact, a large majority of people infected with SARS-CoV-2 rapidly develops a robust and specific antibody and memory B cell response (Guo et al. 2020, Long et al. 2020, Okba et al. 2020, Sokal et al. 2021), with IgA dominating the early neutralizing activity (Sterlin et al. 2020). The induction of humoral immunity may depend on the severity of the disease (Roltgen et al. 2020), however, strong immune response were reported across all disease severities. Some reports indicate a rather quick waning of circulating antibodies (Bruni et al. 2020, Roltgen et al. 2020, Seow et al. 2020), whereas others suggest that protective antibody titers may remain robustly elevated at least for five months (Gudbjartsson et al. 2020, Wajnberg et al. 2020), and B-cell memory likely persists for even longer (Rodda et al. 2020, Sokal et al. 2020). Treatment of severe COVD-19 cases with plasma of convalescent patients has been proposed and clinically tested, but yielded mixed results (Liu et al. 2020a, Rojas et al. 2020, Simonovich et al. 2020).
Beside antibody responses, also T-cell immunity is induced upon infection with SARS-CoV-2 (Cox and Brokstad 2020). While T-cells may contribute to immunopathology in COVID-19 (Gustine and Jones 2021, Mathew et al. 2020, Yang et al. 2020b), they may also play an important role in controlling the infection and, possibly, mediating long-term protection (Chen and John Wherry 2020, Cox and Brokstad 2020, Le Bert et al. 2020, Rydyznski Moderbacher et al. 2020). As it is difficult to functionally relate reactivity to actual protection, the contributions of CD4+ and CD8+ T-lymphocytes requires further investigation. Understanding their role in COVID-19 better, should further direct the development of vaccine candidates.
Owing to the unprecedented importance of controlling this novel viral threat, more than 180 vaccine candidates are currently under development [(Krammer 2020); see also the article by M. Bastian in this volume]. Preliminary reports were insofar promising as they report very strong immune responses across a range of vaccine types (Folegatti et al. 2020, Jackson et al. 2020, Keech et al. 2020, Krammer 2020, Mulligan et al. 2020, Zhu et al. 2020). Two vaccines, both first-of-their-kind mRNA-based approaches (Baden et al. 2020, Polack et al. 2020), and two adenovirus-vectored vaccine candidates showed efficacies in phase 3 clinical studies ranging up to about 90% (Logunov et al. 2020, Voysey et al. 2020). Around the globe, more and more vaccines with different methodologies (including inactivated viruses and purified antigens) are being established and approved. Broad vaccinations that likely offer a high degree of protection at least for a limited period of time, thus, appear to be in feasible reach. If necessary, regular overhauls of the vaccines due to a mutating virus, somewhat akin to the current influenza vaccination approach, is quickly possible at least with non-vectored vaccines and opens the chance for sustained control of the SARS-CoV-2 pandemic.
Summary and outlook
The year 2020 has not only seen a rapid spread of the novel coronavirus SARS-CoV-2, but also a massive and worldwide effort in all fields of biomedical research and beyond. Owing to substantial progress in elucidating the basic biology of virus infection and the molecular pathogenesis of severe COVID-19, possible paths to reliable treatments are only slowly clearing up. In contrast, a broad range of vaccines shown to be safe and efficacious were developed and approved with unprecedented speed. Challenges for the months and years to come include, among others, the elucidation of the frequency, causes and severity of long-term health impairments, and to translate the accumulating knowledge about SARS-CoV-2 biology into therapeutic strategies. With the prospect of a quickly increasing share of the world’s population being vaccinated, the surveillance of possibly emerging vaccine-resistant mutants will further be essential for a sustainable control of SARS-CoV-2.
Conflict of interest
The authors state no conflict of interest.
Both authors are funded by their respective institutions as well as by project DFG BI1693/2-1 from the Deutsche Forschungsgemeinschaft (M. B.).
Both authors equally contributed to literature searches and text writing.
The authors are deeply grateful to Joseph Luna for critical reading of the manuscript.
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Acharya D, Liu G, Gack MU (2020): Dysregulation of type I interferon responses in COVID-19. Nat Rev Immunol 20: 397–398.
Adam DC, Wu P, Wong JY, Lau EHY, Tsang TK, Cauchemez S, Leung GM, Cowling BJ (2020): Clustering and superspreading potential of SARS-CoV-2 infections in Hong Kong. Nat Med 26: 1714–1719.
Almeida JD, Tyrrell DA (1967): The morphology of three previously uncharacterized human respiratory viruses that grow in organ culture. J Gen Virol 1: 175–178.
Althouse BM, Wenger EA, Miller JC, Scarpino SV, Allard A, Hebert-Dufresne L, Hu H (2020): Superspreading events in the transmission dynamics of SARS-CoV-2: Opportunities for interventions and control. PLoS Biol 18: e3000897.
Andersen KG, Rambaut A, Lipkin WI, Holmes EC, Garry RF (2020): The proximal origin of SARS-CoV-2. Nat Med 26: 450–452.
Baden-, LR, El Sahly HM, Essink B, Kotloff K, Frey S, Novak R, Diemert D, Spector SA, Rouphael N, Creech CB, McGettigan J, Khetan S, Segall N, Solis J, Brosz A, Fierro C, Schwartz H, Neuzil K, Corey L, Gilbert P, Janes H, Follmann D, Marovich M, Mascola J, Polakowski L, Ledgerwood J, Graham BS, Bennett H, Pajon R, Knightly C, Leav B, Deng W, Zhou H, Han S, Ivarsson M, Miller J, Zaks T, COVE Study Group (2020): Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N Engl J Med 384(5): 403–416.
Barbaro RP, MacLaren G, Boonstra PS, Iwashyna TJ, Slutsky AS, Fan E, Bartlett RH, Tonna JE, Hyslop R, Fanning JJ, Rycus PT, Hyer SJ, Anders MM, Agerstrand CL, Hryniewicz K, Diaz R, Lorusso R, Combest A, Brodie D, Extracorporeal Life Support Organization (2020): Extracorporeal membrane oxygenation support in COVID-19: an international cohort study of the Extracorporeal Life Support Organization registry. Lancet 396: 1071–1078.
Baric RS, Yount B, Hensley L, Peel SA, Chen W (1997): Episodic evolution mediates interspecies transfer of a murine coronavirus. J Virol 71: 1946–1955.
Bastard P, Rosen LB, Zhang Q, Michailidis E, Hoffmann HH, Zhang Y, Dorgham K, Philippot Q, Rosain J, Beziat V et al. (2020): Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science 370(6515): eabd4585.
Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, Hohmann E, Chu HY, Luetkemeyer A, Kline S, Lopez de Castilla D, Finberg RW, Dierberg K, Tapson V, Hsieh L, Patterson TF, Paredes R, Sweeney DA, Short WR, Touloumi G, Chien Ly D, Ohmagari N, Oh MD, Ruiz-Palacios GM, Benfield T, Fätkenheuer G, Kortepeter MG, Atmar RL, Creech CB, Lundgren J, Babiker AG, Pett S, Neaton JD, Burgess TH, Bonnett T, Green M, Makowski M, Osinusi A, Nayak S, Lane HC, ACTT-1 Study Group Members (2020): Remdesivir for the Treatment of Covid-19 - Final Report. N Engl J Med 383: 1813–1826.
Bilinska K, Butowt R (2020): Anosmia in COVID-19: A Bumpy Road to Establishing a Cellular Mechanism. ACS Chem Neurosci 11(15): 2152–2155.
Blanco-Melo D, Nilsson-Payant B E, Liu W, Uhl S, Hoagland D, Moller R, Jordan T X, Oishi K, Panis M, Sachs D, Wang T T, Schwartz R E, Lim1 JK, Albrecht R A, tenOever B R (2020): Imbalanced host response to SARS-CoV-2 drives development of COVID-19. Cell 181(5): 1036–1045.
Boni MF, Lemey P, Jiang X, Lam TT, Perry BW, Castoe TA, Rambaut A, Robertson DL (2020): Evolutionary origins of the SARS-CoV-2 sarbecovirus lineage responsible for the COVID-19 pandemic. Nat Microbiol 5: 1408–1417.
Braun J, Loyal L, Frentsch M, Wendisch D, Georg P, Kurth F, Hippenstiel S, Dingeldey M, Kruse B, Fauchere F, Baysal E, Mangold M, Henze L, Lauster R, Mall MA, Beyer K, Röhmel J, Voigt S, Schmitz J, Miltenyi S, Demuth I, Müller MA, Hocke A, Witzenrath M, Suttorp N, Kern F, Reimer U, Wenschuh H, Drosten C, Corman VM, Giesecke-Thiel C, Sander LE, Thiel A (2020): SARS-CoV-2-reactive T cells in healthy donors and patients with COVID-19. Nature 587: 270–274.
Bruni M, Cecatiello V, Diaz-Basabe A, Lattanzi G, Mileti E, Monzani S, Pirovano L, Rizzelli F, Visintin C, Bonizzi G, Giani M, Lavitrano m, Faravelli S, Forneris F, Caprioli F, Pelicci PG, Natoli G, Pasqualato S, Mapelli M, Facciotti F (2020): Persistence of Anti-SARS-CoV-2 Antibodies in Non-Hospitalized COVID-19 Convalescent Health Care Workers. J Clin Med 9(10): 3188.
Butowt R, von Bartheld CS (2020): Anosmia in COVID-19: Underlying Mechanisms and Assessment of an Olfactory Route to Brain Infection. Neuroscientist: DOI 10.1177/1073858420956905.
Cacciapaglia G, Cot C, Sannino F (2020): Second wave COVID-19 pandemics in Europe: a temporal playbook. Sci Rep 10: 15514.
Cantuti-Castelvetri L, Ojha R, Pedro LD, Djannatian M, Franz J, Kuivanen S, van der Meer F, Kallio K, Kaya T, Anastasina M, Smura T, Levanov L, Szirovicza L, Tobi A, Kallio-Kokko H, Österlund P, Joensuu M, Meunier FA, Butcher SJ, Winkler MS, Mollenhauer B, Helenius A, Gokce O, Teesalu T, Hepojoki J, Vapalahti O, Stadelmann C, Balistreri G, Simons M (2020): Neuropilin-1 facilitates SARS-CoV-2 cell entry and provides a possible pathway into the central nervous system. Science 370(6518): 856–860.
Carfi A, Bernabei R, Landi F, Gemelli Against CPACSG (2020): Persistent Symptoms in Patients After Acute COVID-19. JAMA 324(6): 603–605 .
Cevik M, Kuppalli K, Kindrachuk J, Peiris M (2020a): Virology, transmission, and pathogenesis of SARS-CoV-2. BMJ 371: m3862.
Cevik M, Tate M, Lloyd O, Maraolo AE, Schafers J, Ho, A. (2021): SARS-CoV-2, SARS-CoV, and MERS-CoV viral load dynamics, duration of viral shedding, and infectiousness: a systematic review and meta-analysis. The Lancet Microbe 2: e13–e22.
Chakraborty S, Gonzalez J, Edwards K, Mallajosyula V, Buzzanco AS, Sherwood R, Buffone C, Kathale N, Providenza S, Xie MM, Andrews JR, Blish CA, Singh U, Dugan H, Wilson PC, Pham TD, Boyd SC, Nadeau KC, Pinsky BA, Zhang S, Memoli MJ, Taubenberger JK, Morales T, Schapiro JM, Tan GS, Jagannathan P, Wang TT (2021): Proinflammatory IgG Fc structures in patients with severe COVID-19. Nat Immunol 22: 67–73.
Chen P, Nirula A, Heller B, Gottlieb RL, Boscia J, Morris J, Huhn G, Cardona J, Mocherla B, Stosor V, Shawa I, Adams AC, van Naarden J, Custer KL, Shen L, Durante M, Oakley G, Schade AE, Sabo J, Patel DR, Klekotka P, Skovronsky DM (2021): SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19. N Engl J Med 384: 229–237.
Chen Z, John Wherry E (2020): T cell responses in patients with COVID-19. Nat Rev Immunol 20: 529–536.
Chu DK, Akl EA, Duda S, Solo K, Yaacoub S, Schunemann HJ, authors C.-S.U.R.G.E.s. (2020): Physical distancing, face masks, and eye protection to prevent person-to-person transmission of SARS-CoV-2 and COVID-19: a systematic review and meta-analysis. Lancet 395: 1973–1987.
Chua RL, Lukassen S, Trump S, Hennig BP, Wendisch D, Pott F, Debnath O, Thurmann L, Kurth F, Volker MT, Kazmierski J, Timmermann B, Twardziok S, Schneider S, Machleidt F, Muller-Redetzky H, Maier M, Krannich A, Schmidt S, Balzer F, Liebig J, Loske J, Suttorp N, Eils J, Ishaque N, Liebert UG, von Kalle C, Hocke A, Witzenrath M, Goffinet C, Drosten C, Laudi S, Lehmann I, Conrad C, Sander LE, Eils R (2020): COVID-19 severity correlates with airway epithelium-immune cell interactions identified by single-cell analysis. Nat Biotechnol 38(8): 970–979.
Consortium W.H.O.S.T., Pan H, Peto R, Henao-Restrepo AM, Preziosi MP, Sathiyamoorthy V, Abdool Karim Q, Alejandria MM, Hernandez Garcia C, Kieny MP et al. (2020): Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results. N Engl J Med 384(6): 497–511.
Cox RJ, Brokstad KA (2020): Not just antibodies: B cells and T cells mediate immunity to COVID-19. Nat Rev Immunol 20: 581–582.
Daly JL, Simonetti B, Antón-Plágaro C, Kavanagh Williamson M, Shoemark DK, Simón-Gracia ., Klein K, Bauer M, Hollandi R, Greber UF, Horvath P, Sessions RB, Helenius A, Hiscox JA, Teesalu T, Matthews DA, Davidson AD, Collins BM, Cullen PJ, Yamauchi Y (2020): Neuropilin-1 is a host factor for SARS-CoV-2 infection. Science 370(6518): 861–865.
Davies NG, Barnard RC, Jarvis CI, Kucharski AJ, Munday J, Pearson CAB, Russell TW, Tully DC, Abbott S, Gimma A, Waites W, Wong KLM, van Zandvoort K, CMMID COVID-19 Working Group, Eggo RM, Funk S, Jit M, Atkins KE, Edmunds WJ (2020): Estimated transmissibility and severity of novel SARS-CoV-2 Variant of Concern 202012/01 in England. medRxiv: DOI 10.1101/2020.12.24.20248822 (preprint).
de Vries RD (2020): SARS-CoV-2-specific T-cells in unexposed humans: presence of cross-reactive memory cells does not equal protective immunity. Signal Transduct Target Ther 5: 224.
Dehning J, Zierenberg J, Spitzner FP, Wibral M, Neto JP, Wilczek M, Priesemann V (2020): Inferring change points in the spread of COVID-19 reveals the effectiveness of interventions. Science 369.
Docherty AB, Harrison EM, Green CA, Hardwick HE, Pius R, Norman L, Holden KA, Read JM, Dondelinger F, Carson G, Merson L, Lee J, Plotkin D, Sigfrid L, Halpin S, Jackson C, Gamble C, Horby PW, Nguyen-Van-Tam JS, Ho A, Russell CD, Dunning J, Openshaw PJM, Baillie JK, Semple MG (2020): Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study. BMJ 369: m1985.
Edridge AWD, Kaczorowska J, Hoste ACR, Bakker M, Klein M, Loens K, Jebbink MF, Matser A, Kinsella CM, Rueda P, Ieven M, Goossens H, Prins M, Sastre P, Deijs M, van der Hoek L (2020): Seasonal coronavirus protective immunity is short-lasting. Nat Med 26(11): 1691–1693.
European Centre for Disease Prevention and Control (2020): COVID-19 Situation Dashboard. https://qap.ecdc.europa.eu/public/extensions/COVID-19/COVID-19.html#glo… (accessed 22.03.2021).
Fehr AR, Perlman S (2015): Coronaviruses: an overview of their replication and pathogenesis. Methods Mol Biol 1282: 1–23.
Fennelly KP (2020): Particle sizes of infectious aerosols: implications for infection control. Lancet Respir Med 8(9): 914–924.
Fiege JK, Thiede JM, Nanda H, Matchett WE, Moore PJ, Montanari NR, Thielen BK, Daniel J, Stanley E, Hunter RC, Menachery VD, Shen SS, Bold TD, Langlois RA (2020): Single cell resolution of SARS-CoV-2 tropism, antiviral responses, and susceptibility to therapies in primary human airway epithelium. PLoS Pathog 17(1): e1009292.
Flaxman S, Mishra S, Gandy A, Unwin HJT, Mellan TA, Coupland H, Whittaker C, Zhu H, Berah T, Eaton JW,Monod M, Imperial College COVID-19 Response Team, Ghani AC, Donnelly CA, Riley S, Vollmer MAC, Ferguson NM, Okell LC, Bhatt S (2020): Estimating the effects of non-pharmaceutical interventions on COVID-19 in Europe. Nature 584(7820): 257–261.
Folegatti PM, Ewer KJ, Aley PK, Angus B, Becker S, Belij-Rammerstorfer S, Bellamy D, Bibi S, Bittaye M, Clutterbuck EA, Dold C, Faust SN, Finn A, Flaxman AL, Hallis B, Heath P, Jenkin D, Lazarus R, Makinson R, Minassian AM, Pollock KM, Ramasamy M, Robinson H, Snape M, Tarrant R, Voysey Merryn, Green C, Douglas AD, Hill AVS, Lambe T, Gilbert SC, Pollard AJ, Oxford COVID Vaccine Trial Group (2020): Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial. Lancet 396(10249): 467–478.
Gabarre P, Dumas G, Dupont T, Darmon M, Azoulay E, Zafrani L (2020): Acute kidney injury in critically ill patients with COVID-19. Intensive Care Med 46: 1339–1348.
Galani IE, Rovina N, Lampropoulou V, Triantafyllia V, Manioudaki M, Pavlos E, Koukaki E, Fragkou PC, Panou V, Rapti V,Koltsida O, Mentis A, Koulouris N, Tsiodras S, Koutsoukou A, Andreakos E (2021): Untuned antiviral immunity in COVID-19 revealed by temporal type I/III interferon patterns and flu comparison. Nat Immunol 22(1): 32–40.
Ghinai I, Woods S, Ritger KA, McPherson TD, Black SR, Sparrow L, Fricchione MJ, Kerins JL, Pacilli M, Ruestow PS, Arwady MA, Beavers SF, Payne DC, Kirking HL, Layden JE (2020): Community Transmission of SARS-CoV-2 at Two Family Gatherings - Chicago, Illinois, February-March 2020. MMWR Morb Mortal Wkly Rep 69(15): 446–450.
Gudbjartsson DF, Norddahl GL, Melsted P, Gunnarsdottir K, Holm H, Eythorsson E, Arnthorsson AO, Helgason D, Bjarnadottir K, Ingvarsson RF et al. (2020): Humoral Immune Response to SARS-CoV-2 in Iceland. N Engl J Med 383(18): 1724–1734.
Guenther T, Czeck-Sioli M, Indenbirken D, Robitailles A, Tenhaken P, Exner M, Ottinger M, Fischer N, Grundhoff A, Brinkmann M (2020): SARS‐CoV‐2 outbreak investigation in a German meat processing plant. EMBO Mol Med 12(12): e13296.
Guo L, Ren L, Yang S, Xiao M, Chang Yang F, Dela Cruz CS, Wang Y, Wu C, Xiao Y, Zhang L, Han L, Dang S, Xu Y, Yang QW, Xu SY, Zhu HD, Xu YC, Jin Q, Sharma L, Wang L, Wang J (2020): Profiling Early Humoral Response to Diagnose Novel Coronavirus Disease (COVID-19). Clin Infect Dis 71(15): 778–785.
Gustine JN, Jones D (2021): Immunopathology of Hyperinflammation in COVID-19. Am J Pathol 191: 4–17.
Hadfield J, Megill C, Bell SM, Huddleston J, Potter B, Callender C, Sagulenko P, Bedford T, Neher RA (2018): Nextstrain: real-time tracking of pathogen evolution. Bioinformatics 34: 4121–4123.
Hadjadj J, Yatim N, Barnabei L, Corneau A, Boussier J, Smith N, Pere H, Charbit B, Bondet V, Chenevier-Gobeaux C, Breillat P, Carlier N, Gauzit R, Morbieu C, Pene F, Marin N, Roche N, Szwebel TA, Merkling SH, Treluyer JM, Veyer D, Mouthon L, Blanc C, Tharaux PL, Rozenberg F, Fischer A, Duffy D, Rieux-Laucat F, Kerneis S, Terrier B (2020): Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients. Science 369(6504): 718–724.
Hall M, Pritchard M, Dankwa EA, Baillie JK, Carson G, Citarella BW, Docherty A, Donnelly CA, Dunning J, Fraser C, Hardwick H, Harrison EM, Holden KA, Kartsonaki C, Kennon K, Lee J, McLean K, Openshaw PJM, Plotkin D, Rojek A, Russell CD, Semple MG, Sigfrid L, Smith S, Horby P, Olliaro P, Merson L (2020): ISARIC Clinical Data Report 20 November 2020. medRxiv: DOI 10.1101/2020.07.17.20155218 (preprint).
Hamner L, Dubbel P, Capron I, Ross A, Jordan A, Lee J, Lynn J, Ball A, Narwal S, Russell S, Patrick D, Leibrand H (2020): High SARS-CoV-2 Attack Rate Following Exposure at a Choir Practice - Skagit County, Washington, March 2020. MMWR Morb Mortal Wkly Rep 69(19): 606–610.
Hayn M, Hirschenberger M, Koepke L, Straub JH, Nchioua R, Christensen MH, Klute S, Bozzo CP, Aftab W, Zech F, Conzelmann C, Müller JA, Badarinarayan SS, Stürzel CM, Forne I, Stenger S, Conzelmann K, Münch J, Sauter D, Schmidt FI, Imhof A, Kirchhoff F, Sparrer KM (2020): Imperfect innate immune antagonism renders SARS-CoV-2 vulnerable towards IFN-γ and -λ. bioRxiv: DOI 10.1101/2020.10.15.340612 (preprint).
Herrmann J, Mori V, Bates JHT, Suki B (2020): Modeling lung perfusion abnormalities to explain early COVID-19 hypoxemia. Nat Commun 11: 4883.
Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH Nitsche, A, Müller MA, Drosten C, Pöhlmann S (2020): SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell 181(2): 271–280.e28.
Hönzke K, Obermayer B, Mache C, Fatykhova D, Kessler M, Dökel S, Wyler E, Hoffmann K, Schulze J, Mieth M, Hellwig K, Biere B, Brunotte L, Mecate-Zambrano A, Hoppe J, Dohmen M, Hinze C, Elezkurtaj S, Tönnies M, Bauer T, Eggeling S, Tran H, Schneider P, Neudecker J, Rückert J, Schmidt-Ott K, Busch J, Klauschen F, Horst D, Radbruch H, Heppner F, Corman VM, Niemeyer D, Müller MA, Goffinet C, Beule D, Landthaler M, Ludwig S, Niedobitek G, Suttorp N, Witzenrath M, Gruber A, Drosten C, Sander LE, Wolff T, Hippenstiel S, Hocke AC (2020): Human Lungs Show Limited Permissiveness for SARS-CoV-2 Due to Scarce ACE2 Levels But Strong Virus-Induced Immune Activation in Alveolar Macrophages. SSRN: DOI 10.2139/ssrn.3687020 (preprint).
Hou YJ, Chiba S, Halfmann P, Ehre C, Kuroda M, Dinnon KH 3rd, Leist SR, Schafer A, Nakajima N, Takahashi K, Lee RE, Mascenik TM, Graham R, Edwards CE, Tse LV, Okuda K, Markmann AJ, Bartelt L, de Silva A, Margolis DM, Boucher RC, Randell SH, Suzuki T, Gralinski LE, Kawaoka Y, Baric RS (2020a): SARS-CoV-2 D614G variant exhibits efficient replication ex vivo and transmission in vivo. Science 370(6523): 1464–1468.
Hou YJ, Okuda K, Edwards CE, Martine, DR, Asakura T, Dinnon KH 3rd, Kato T, Lee RE, Yount BL, Mascenik TM, Chen G, Olivier KN, Ghio A, Tse LV, Leist SR, Gralinski LE, Schäfer A, Dang H, Gilmore R, Nakano S, Sun L, Fulcher ML, Livraghi-Butrico A, Nicely NI, Cameron M, Cameron C, Kelvin DJ, de Silva A, Margolis DM, Markmann A, Bartelt L, Zumwalt R, Martinez FJ, Salvatore SP, Borczuk A, Tata PR, Sontake V, Kimple A, Jaspers I, O’Neal W, Randell SH, Boucher RC, Baric RS (2020b): SARS-CoV-2 Reverse Genetics Reveals a Variable Infection Gradient in the Respiratory Tract. Cell 182(2): 429–446.e14.
Huang C, Huang L, Wang Y, Li X, Ren L, Gu X, Kang L, Guo L, Liu M, Zhou X, Luo J, Huang Z, Tu S, Zhao Y, Chen L, Xu D, Li Y, Li C, Peng L, Li Y, Xie W, Cui D, Shang L, Fan G, Xu J, Wang G, Wang Y, Zhong J, Wang C, Wang J, Zhang D, Cao B (2021): 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study. Lancet 397(10270): 220–232.
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, WangJ, Cao B (2020): Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395(10223): 497–506.
Jackson LA, Anderson EJ, Rouphael NG, Roberts PC, Makhene M, Coler RN, McCullough MP, Chappell JD, Denison MR, Stevens LJ, Pruijssers AJ, McDermott A, Flach B, Doria-Rose NA, Corbett KS, Morabito KM, O’Dell S, Schmidt SD, Swanson 2nd PA, Padilla M, Mascola JR, Neuzil KM, Bennett H, Sun W, Peters E, Makowski M, Albert J, Cross K, Buchanan W, Pikaart-Tautges R, Ledgerwood JE, Graham BS, Beigel JH, mRNA-1273 Study Group (2020): An mRNA Vaccine against SARS-CoV-2 - Preliminary Report. N Engl J Med 383(20): 1920–1931.
James A, Eagle L, Phillips C, Hedges DS, Bodenhamer C, Brown R, Wheeler JG, Kirking H (2020): High COVID-19 Attack Rate Among Attendees at Events at a Church - Arkansas, March 2020. MMWR Morb Mortal Wkly Rep 69: 632–635.
Kalil AC, Patterson TF, Mehta AK, Tomashek KM, Wolfe CR. Ghazaryan V, Marconi VC, Ruiz-Palacios GM, Hsieh L, Kline S et al. (2020): Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19. N Engl J Med 384(9): 795–807.
Kasper MR, Geibe JR, Sears CL, Riegodedios AJ, Luse T, Von Thun AM, McGinnis MB, Olson N, Houskamp D, Fenequito R, Burgess TH, Armstrong AW, DeLong G, Hawkins RJ, Gillingham BL (2020): An Outbreak of Covid-19 on an Aircraft Carrier. N Engl J Med 383(25): 2417–2426.
Keech C, Albert G, Cho I, Robertson A, Reed P, Neal S, Plested JS, Zhu M, Cloney-Clark S, Zhou H, Smith G, Patel N, Frieman MB, Haupt RE, Logue J, McGrath M, Weston S, Piedra PA, Desai C, Callahan K, Lewis M, Price-Abbott P, Formica N, Shinde V, Fries L, Lickliter JD, Griffin P, Wilkinson B, Glenn GM (2020): Phase 1–2 Trial of a SARS-CoV-2 Recombinant Spike Protein Nanoparticle Vaccine. N Engl Med 383: 2320–2332.
Keeley AJ, Evans CM, de Silva TI (2020): Asymptomatic SARS-CoV-2 infection: the tip or the iceberg? Thorax 75: 621–622.
Klompas M, Baker MA, Rhee C (2020): Airborne Transmission of SARS-CoV-2: Theoretical Considerations and Available Evidence. JAMA 324(5): 441–442.
Korber B, Fischer WM, Gnanakaran S, Yoon H, Theiler J, Abfalterer W, Hengartner N, Giorgi EE, Bhattacharya T, Foley B, Hastie KM, Parker MD, Partridge DG, Evans CM, Freeman TM, de Silva TI (2020): Tracking Changes in SARS-CoV-2 Spike: Evidence that D614G Increases Infectivity of the COVID-19 Virus. Cell 182(4): 812–827.
Krammer F (2020): SARS-CoV-2 vaccines in development. Nature 586: 516–527.
Kupferschmidt K (2020): Why do some COVID-19 patients infect many others, whereas most don’t spread the virus at all? Science: DOI 10.1126/science.abc8931.
Lamers MM, Beumer J, van der Vaart J, Knoops K, Puschhof J, Breugem TI, Ravelli RBG, Paul van Schayck J, Mykytyn AZ, Duimel HQ, van Donselaar E, Riesebosch S, Kuijpers HJH, Schipper D, van de Wetering WJ, de Graaf M, Koopmans M, Cuppen E, Peters PJ, Haagmans BL, Clevers H (2020): SARS-CoV-2 productively infects human gut enterocytes. Science 369(6499): 50–54.
Larsen MD, de Graaf EL, Sonneveld ME, Plomp HR, Nouta J, Hoepel W, Chen HJ, Linty F, Visser R, Brinkhaus M, Sustic T, de Taeye SW, Bentlage AEH, Toivonen S, Koeleman CAM, Sainio S, Kootstra NA, Brouwer PJM, Geyer CE, Derksen NIL, Wolbink G, de Winther M, Sanders RW, van Gils MJ, de Bruin S, Vlaar APJ, UMC COVID-19 biobank study group, Rispens T, den Dunnen J, Zaaijer HL, Wuhrer M, van der Schoot CE, Vidarsson G (2020): Afucosylated IgG characterizes enveloped viral responses and correlates with COVID-19 severity. Science 371(6532): eabc8378.
Le Bert N, Tan AT, Kunasegaran K, Tham CYL, Hafezi M, Chia A., ChngMHY, Lin M, Tan N, Linster M, Chia WN, Chen MIC, Wang LF, Ooi EE, Kalimuddin S, Tambyah PA, Low JGH, Tan YJ, Bertoletti A (2020): SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls. Nature 584: 457–462.
Lee JS, Shin EC (2020): The type I interferon response in COVID-19: implications for treatment. Nat Rev Immunol 20: 585–586.
Lei X, Dong X, Ma R, Wang W, Xiao X, Tian Z, Wang C, Wang Y, Li L, Ren L, Guo F, Zhao Z, Zhou Z, Xiang Z, Wang J (2020): Activation and evasion of type I interferon responses by SARS-CoV-2. Nat Commun 11: 3810.
Levin AT, Hanage WP, Owusu-Boaitey N, Cochran KB, Walsh SP, Meyerowitz-Katz G (2020): Assessing the age specificity of infection fatality rates for COVID-19: systematic review, meta-analysis, and public policy implications. Eur J Epidemiol 35: 1123–1138.
Li Q, Guan X, Wu P, Wang X, Zhou L, Tong Y, Ren R, Leung KSM, Lau EHY, Wong JY, Xing X, Xiang N, Wu Y, Li C, Chen Q, Li D, Liu T, Zhao J, Liu M, Tu W, Chen C, Jin L, Yang R, Wang Q, Zhou S, Wang R, Liu H, Luo Y, Liu Y, Shao G, Li H, Tao Z, Yang Y, Deng Z, Liu B, Ma Z, Zhang Y, Shi G, Lam TTY, Wu JT, Gao GF, Cowling BJ, Yang B, Leung GM, Feng Z (2020a): Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia. N Engl J Med 382(13): 1199–1207.
Li X, Geng M, Peng Y, Meng L, Lu S (2020b): Molecular immune pathogenesis and diagnosis of COVID-19. J Pharm Anal 10: 102–108.
Liang X, Shi L, Wang Y, Xiao W, Duan G, Yang H, Wang Y (2020): The association of hypertension with the severity and mortality of COVID-19 patients: Evidence based on adjusted effect estimates. J Infect 81: e44-e47.
Liao M, Liu Y, Yuan J, Wen Y, Xu G, Zhao J, Cheng L, Li J, Wang X, Wang F, Liu L, Amit I, Zhang S, Zhang Z (2020): Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19. Nat Med 26: 842–844.
Lipsitch M, Grad YH, Sette A, Crotty S (2020): Cross-reactive memory T cells and herd immunity to SARS-CoV-2. Nat Rev Immunol 20: 709–713.
Liu STH, Lin HM, Baine I, Wajnberg A, Gumprecht JP, Rahman F, Rodriguez D, Tandon P, Bassily-Marcus A, Bander J, Sanky C, Dupper A, Zheng A, Nguyen FT, Amanat F, Stadlbauer D, Altman DR, Chen BK, Krammer F, Mendu DR, Firpo-Betancourt A, Levin MA, Bagiella E, Casadevall A, Cordon-Cardo C, Jhang JS, Arinsburg SA, Reich DL, Aberg JA, Bouvier NM (2020a): Convalescent plasma treatment of severe COVID-19: a propensity score-matched control study. Nat Med 26(11): 1708–1713.
Liu Y, Eggo RM, Kucharski AJ (2020b): Secondary attack rate and superspreading events for SARS-CoV-2. Lancet 395(10227): e47.
Logunov DY, Dolzhikova IV, Zubkova OV, Tukhvatullin AI, Shcheblyakov DV, Dzharullaeva AS, Grousova DM, Erokhova AS, Kovyrshina AV, Botikov AG, Izhaeva FM, Popova O, Ozharovskaya TA, Esmagambetov IB, Favorskaya IA, Zrelkin DI, Voronina DV, Shcherbinin DN, Semikhin AS, Simakova YV, Tokarskaya EA, Lubenets N, Egorova DA, Shmarov MM, Nikitenko NA, Morozova LF, Smolyarchuk EA, Kryukov EV, Babira VF, Borisevich SV, Naroditsky BS, Gintsburg AL (2020): Safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine in two formulations: two open, non-randomised phase 1/2 studies from Russia. Lancet 396(10255): 887–897.
Long QX, Liu BZ Deng HJ, Wu GC, Deng K, Chen YK, Liao P, Qiu JF, Lin Y, Cai XF, Wang DQ, Hu Y, Ren JH, Tang N, Xu YY, Yu LH, Mo Z, Gong F, Zhang XL, Tian WG, Hu L, Zhang XX, Xiang JL, Du HX, Liu HW, Lang CH, Luo XH, Wu SB, Cui XP, Zhou Z, Zhu MM, Wang J, Xue CJ, Li XF, Wang L, Li ZJ, Wang K, Niu CC, Yang QJ, Tang XJ, Zhang Y, Liu XM, Li JJ, Zhang DC, Zhang F, Liu P, Yuan J, Li Q, Hu JL, Chen J, Huang AI (2020): Antibody responses to SARS-CoV-2 in patients with COVID-19. Nat Med 26(6): 845–848.
Looi MK (2020): Covid-19: Is a second wave hitting Europe? BMJ 371: m4113.
Lucas C, Klein J, Sundaram M, Liu F, Wong P, Silva J, Mao T, Oh JE, Tokuyama M, Lu P, Venkataraman A, Park A, Israelow B, Wyllie AL, Vogels CBF, Muenker MC, Casanovas-Massana A, Schulz WL, Zell J, Campbell M, Fournier JB, Yale IMPACT Research Team, Grubaugh ND, Farhadian S, Wisnewski AV, Dela Cruz C, Omer S, Ko AI, Ring A, Iwasaki A (2020): Kinetics of antibody responses dictate COVID-19 outcome. medRxiv: DOI 10.1101/2020.12.18.20248331(preprint).
Makaronidis J, Mok J, Balogun N, Magee CG, Omar RZ, Carnemolla A, Batterham RL (2020): Seroprevalence of SARS-CoV-2 antibodies in people with an acute loss in their sense of smell and/or taste in a community-based population in London, UK: An observational cohort study. PLoS Med 17: e1003358.
Mangalmurti N, Hunter CA (2020): Cytokine Storms: Understanding COVID-19. Immunity 53: 19–25.
Masters PS, Perlman S (2013): Coronaviridae. In: Knipe DM, Howley PM (eds.): Fields Virology. Wolters Kluwer Health/Lippincott Williams & Wilkins Philadelphia, 825–884.
Mateus J, Grifoni A, Tarke A, Sidney J, Ramirez SI, Dan JM, Burger ZC, Rawlings SA, Smith DM, Phillips E, Mallal S, Lammers M, Rubiro P, Quiambao L, Sutherland A, Yu ED, da Silva Antunes R, Greenbaum J, Frazier A, Markmann AJ, Premkumar L, de Silva A, Peters B, Crotty S, Sette A, Weiskopf D (2020): Selective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans. Science 370(6512): 89–94.
Mathew D, Giles JR, Baxter AE, Oldridge DA, Greenplate AR, Wu JE, Alanio C, Kuri-Cervantes L, Pampena MB, D’Andrea KManne S, Chen Z, Huang YJ, Reilly JP, Weisman AR, Ittner CAG, Kuthuru O, Dougherty J, Nzingha K, Han N, Kim J, Pattekar A, Goodwin EC, Anderson EM, Weirick ME, Gouma S, Arevalo CP, Bolton MJ, Chen F, Lacey SF, Ramage H, Cherry S, Hensley SE, Apostolidis SA, Huang AC, Vella LA, UPenn COVID Processing Unit, Betts MR, Meyer NJ, Wherry EJ (2020): Deep immune profiling of COVID-19 patients reveals distinct immunotypes with therapeutic implications. Science 369(6508): eabc8511.
McKechnie JL, Blish CA (2020): The Innate Immune System: Fighting on the Front Lines or Fanning the Flames of COVID-19? Cell Host Microbe 27: 863–869.
Meinhardt J, Radke J, Dittmayer C, Franz J, Thomas C, Mothes R, Laue M, Schneider J, Brunink S, Greuel S, Lehmann M, Hassan O, Aschman T, Schumann E, Chua RL, Conrad C, Eils R, Stenzel W, Windgassen M, Rößler L, Goebel HH, Gelderblom HR, Martin H, Nitsche A, Schulz-Schaeffer WJ, Hakroush S, Winkler MS, Tampe B, Scheibe F, Körtvelyessy P, Reinhold D, Siegmund B, Kühl AA, Elezkurtaj S, Horst D, Oesterhelweg L, Tsokos M, Ingold-Heppner B, Stadelmann C, Drosten C, Corman VM, Radbruch H, Heppner FL (2020): Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19. Nat Neurosci 24(2): 168–175.
Mitrani RD, Dabas N, Goldberger JJ (2020): COVID-19 cardiac injury: Implications for long-term surveillance and outcomes in survivors. Heart Rhythm 17(11): 1984–1990.
Moore BJB, June CH (2020): Cytokine release syndrome in severe COVID-19. Science 368(6490): 473–474.
Moriyama M, Hugentobler WJ, Iwasaki A (2020): Seasonality of Respiratory Viral Infections. Annu Rev Virol 7(1): 83–101.
Mulligan MJ, Lyke KE, Kitchin N, Absalon J, Gurtman A, Lockhart SP, Neuzil K, Raabe V, Bailey R, Swanson KA Li P, Koury K, Kalina W, Cooper D, Fontes-Garfias C, Shi PY, Tureci O, Tompkins KR, Walsh EE, Frenck R, Falsey AR, Dormitzer PR, Gruber WC, Sahin U, Jansen K (2020): Phase 1/2 Study of COVID-19 RNA Vaccine BNT162b1 in Adults. Nature 586: 589–593.
Nature Medicine Editorial (2020): Meeting the challenge of long COVID. Nat Med 26: 1803.
Neufeldt CJ, Cerikan B, Cortese M, Frankish J, Lee JY, Plociennikowska A, Heigwer F, Joecks S, Burkart SS, Zander DY Gendarme M, El Debs B, Halama N, Merle U, Boutros M, Binder M, Bartenschlager R (2020): SARS-CoV-2 infection induces a pro-inflammatory cytokine response through cGAS-STING and NF-κB. bioRxiv: DOI 10.1101/2020.07.21.212639 (preprint).
Ng KW, Faulkner N, Cornish GH, Rosa A, Harvey R, Hussain S, Ulferts R, Earl C, Wrobel AG, Benton DJ, Roustan C, Bolland W, Thompson R, Agua-Doce A, Hobson P, Heaney J, Rickman H, Paraskevopoulou S, Houlihan CF, Thomson K, Sanchez E, Shin GY, Spyer MJ, Joshi D, O’Reilly N, Walker PA, Kjaer S, Riddell A, Moore C, Jebson BR, Wilkinson M, Marshall LR, Rosser EC, Radziszewska A, Peckham H, Ciurtin C, Wedderburn LR, Beale R, Swanton C, Gandhi S, Stockinger B, McCauley J, Gamblin SJ, McCoy LE, Cherepanov P, Nastouli E, Kassiotis G (2020): Preexisting and de novo humoral immunity to SARS-CoV-2 in humans. Science 370(6522): 1339–1343.
Nouailles G, Wyler E, Pennitz P, Postmus D, Vladimirova D, Kazmierski J, Pott F, Dietert K, Mülleder M, Farztdinov V Obermayer B, Wienhold SM, Andreotti S, Hofler T, Sawitzki B, Drosten C, Sander LE, Suttorp N, Ralser M, Beule D, Grubr AD, Goffinet C, Landthaler M, Trimpert J, Witzenrath M (2020): Longitudinal omics in Syrian hamsters integrated with human data unravel complexity of moderate immune responses to SARS-CoV-2. bioRxiv: DOI 10.1101/2020.12.18.423524 (preprint).
O’Driscoll M, Ribeiro Dos Santos G, Wang L., Cummings DAT, Azman AS, Paireau J, Fontanet A, Cauchemez S, Salje H (2020): Age-specific mortality and immunity patterns of SARS-CoV-2. Nature 590: 140–145.
Okba NMA, Muller MA, Li W, Wang C, GeurtsvanKessel CH, Corman VM, Lamers MM, Sikkema RS, de Bruin E, Chandler FD, Yazdanpanah Y, Le Hingrat Q, Descamps D, Houhou-Fidouh N, Reusken CBEM, Bosch BJ, Drosten C, Koopmans MPG, Haagmans BL (2020): Severe Acute Respiratory Syndrome Coronavirus 2-Specific Antibody Responses in Coronavirus Disease Patients. Emerg Infect Dis 26(7): 1478–1488.
Oude Munnink BB, Sikkema RS, Nieuwenhuijse DF, Molenaar RJ, Munger E, Molenkamp R, van der Spek A, Tolsma P, Rietveld A, Brouwer M, Bouwmeester-Vincken N, Harders F, Hakze-van der Honing R, Wegdam-Blans MCA, Bouwstra RJ, GeurtvanKessel C, van der Eijk AA, Velkers FC, Smit LAM, Stegeman A, van der Poel WHM, Koopmans MPG (2020): Transmission of SARS-CoV-2 on mink farms between humans and mink and back to humans. Science 371(6525): 172–177.
Pairo-Castineira E, Clohisey S, Klaric L, Bretherick AD, Rawlik K, Pasko D, Walker S, Parkinson N, Fourman MH, Russell CD et al. (2020): Genetic mechanisms of critical illness in Covid-19. Nature 591(7848): 92–98.
Park A, Iwasaki A (2020): Type I and Type III Interferons - Induction, Signaling, Evasion, and Application to Combat COVID-19. Cell Host Microbe 27: 870–878.
Park SW, Bolker BM, Champredon D, Earn DJD, Li M, Weitz JS, Grenfell BT, Dushoff J (2020a): Reconciling early-outbreak estimates of the basic reproductive number and its uncertainty: framework and applications to the novel coronavirus (SARS-CoV-2) outbreak. J R Soc Interface 17: 20200144.
Park SY, Kim YM, Yi S, Lee S, Na BJ, Kim CB, Kim JI, Kim HS, Kim YB, Park Y, Huh IS, Kim HK, Yoon HJ, Jang H, Kim K, Chang Y, Kim I, Lee H, Gwack J, Kim SS, Kim M, Kweon S, Choe YJ, Park O, Park YJ, Jeong EK (2020b): Coronavirus Disease Outbreak in Call Center, South Korea. Emerg Infect Dis 26(8): 1666–1670.
Pastor-Barriuso R, Perez-Gomez B, Hernan M.A, Perez-Olmeda M, Yotti R, Oteo-Iglesias J, Sanmartin JL, Leon-Gomez I, Fernandez-Garcia A, Fernandez-Navarro P, Cruz I, Martin M, Delgado-Sanz C, Fernandez de Larrea N, Paniagua JL, Munoz-Montalvo JF, Blanco F, Larrauri A, Pollan M (2020): Infection fatality risk for SARS-CoV-2 in community dwelling population of Spain: nationwide seroepidemiological study. BMJ 371: m4509.
Perico L, Benigni A, Casiraghi F, Ng LFP, Renia L, Remuzzi G (2021): Immunity, endothelial injury and complement-induced coagulopathy in COVID-19. Nat Rev Nephrol 17: 46–64.
Phua J, Weng L, Ling L, Egi M, Lim CM, Divatia JV, Shrestha BR, Arabi YM, Ng J, Gomersall CD, Nishimura M, Koh Y, Du B, Asian Critical Care Clinical Trials Group (2020): Intensive care management of coronavirus disease 2019 (COVID-19): challenges and recommendations. Lancet Respir Med 8(5): 506–517.
Pislar A, Mitrovic A, Sabotic J, Pecar Fonovic U, Perisic Nanut M, Jakos T, Senjor E, Kos J (2020): The role of cysteine peptidases in coronavirus cell entry and replication: The therapeutic potential of cathepsin inhibitors. PLoS Pathog 16: e1009013.
Polack FP, Thomas SJ, Kitchin N, Absalon J, Gurtman A, Lockhart S, Perez JL, Perez Marc G, Moreira ED, Zerbini C, Bailey R, Swanson KA, Roychoudhury S, Koury K, Li P, Kalina WV, Cooper D, Frenck Jr RW, Hammitt LL, Türeci Ö, Nell H, Schaefer A, Ünal S, Tresnan DB, Mather S, Dormitzer PR, Sahin U, Jansen KU, Gruber WC, C4591001 Clinical Trial Group (2020): Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med 383(27): 2603–2615.
Pollan M, Perez-Gomez B, Pastor-Barriuso R, Oteo J, Hernan MA, Perez-Olmeda M, Sanmartin JL, Fernandez-Garcia A, Cruz I, Fernandez de Larrea N, Molina M, Rodriguez-Cabrera F, Martin M, Merino-Amador P, Paniagua JL, Munoz-Montalvo JF, Blanco F, Yotti R, ENE-COVID Study Group (2020): Prevalence of SARS-CoV-2 in Spain (ENE-COVID): a nationwide, population-based seroepidemiological study. Lancet 396(10250): 535–544.
Popa A, Genger JW, Nicholson MD, Penz T, Schmid D Aberle, SW, Agerer B, Lercher A, Endler L, Colaco H, Smyth M, Schuster M, Grau ML, Martínez-Jiménez F, Pich O, Borena W, Pawelka E, Keszei Z, Senekowitsch M, Laine J,
Aberle JH, Redlberger-Fritz M, Karolyi M, Zoufaly A, Maritschnik S, Borkovec M, Hufnagl P, Nairz M, Weiss G, Wolfinger MT, von Laer D, Superti-Furga G, Lopez-Bigas N, Puchhammer-Stöckl E, Allerberger F, Michor F, Bock C, Bergthaler A (2020): Genomic epidemiology of superspreading events in Austria reveals mutational dynamics and transmission properties of SARS-CoV-2. Sci Transl Med 12(573).
Potey PM, Rossi AG, Lucas CD, Dorward DA (2019): Neutrophils in the initiation and resolution of acute pulmonary inflammation: understanding biological function and therapeutic potential. J Pathol 247: 672–685.
Prather KA, Marr LC, Schooley RT, McDiarmid MA, Wilson ME, Milton DK (2020): Airborne transmission of SARS-CoV-2. Science 370: 303–304.
Puntmann VO, Carerj ML, Wieters I, Fahim M, Arendt C, Hoffmann J, Shchendrygina A, Escher F, Vasa-Nicotera M, Zeiher AM, Vehreschild M, Nagel E (2020): Outcomes of Cardiovascular Magnetic Resonance Imaging in Patients Recently Recovered From Coronavirus Disease 2019 (COVID-19). JAMA Cardiol 5(11): 1265–1273.
Recovery CG, Horby PW, Pessoa-Amorim G, Peto L, Brightling CE, Sarkar R, Thomas K, Jeebun V, Ashish A, Tully R, Chadwick D, Sharafat M, Stewart R, Rudran B, Baillie JK, Buch MH, Chappell LC, Day JN, Furst SN, Jaki T, Jeffery K, Juszczak E, Shen Lim W, Montgomery A, Mumford A, Rowan K, Thwaites G, Mafham M, Haynes R, Landray MJ (2021): Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): preliminary results of a randomised, controlled, open-label, platform trial. medRxiv: DOI 10.1101/2021.02.11.21249258 (preprint).
Rodda LB, Netland J, Shehata L, Pruner KB, Morawski PA, Thouvenel CD, Takehara KK, Eggenberger J, Hemann EA, Waterman HR, Fahning ML, Chen Y, Hale M, Rathe J, Stokes C, Wrenn S, Fiala B, Carter L, Hamerman JA, King NP, Gale M, Campell DJ, Rawlings DJ, Pepper M (2020): Functional SARS-CoV-2-Specific Immune Memory Persists after Mild COVID-19. Cell 184(1).
Rojas M, Rodriguez Y, Monsalve DM, Acosta-Ampudia Y, Camacho B, Gallo JE, Rojas-Villarraga A, Ramirez-Santana C, Diaz-Coronado JC, Manrique R, Mantilla RD, Shoenfeld Y, Anaya JM (2020): Convalescent plasma in Covid-19: Possible mechanisms of action. Autoimmun Rev 19(7): 102554.
Roltgen K, Powell AE, Wirz OF, Stevens BA, Hogan CA, Najeeb J, Hunter M, Wang H, Sahoo MK, Huang C, Yamamoto F, Manohar M, Manalac J, Otrelo-Cardoso AR, Pham TD, Rustagi A, Rogers AJ, Shah NH, Blish CA, Cochran JR, Jardetzky TS, Zehnder JL, Wang TT, Narasimhan B, Gombar S, Tibshirani R, Nadeau KC, Kim PS, Pindsky BA, Boyd SD (2020): Defining the features and duration of antibody responses to SARS-CoV-2 infection associated with disease severity and outcome. Sci Immunol 5(54): eabe0240.
Rubin SJS, Falkson SR, Degner NR, Blish C (2020): Clinical characteristics associated with COVID-19 severity in California. J Clin Transl Sci: 1–4.
Rydyznski Moderbacher C, Ramirez SI, Dan JM, Grifoni A Hastie KM, Weiskopf D, Belanger S, Abbott RK, Kim C, Choi J, Kato Y, Crotty EG, Kim C, Rawlings SA, Mateus J, Tse LPV, Frazier A, Baric R, Peters B, Greenbaum J, Ollmann Saphire E, Smith DM, Sette A, Crotty S (2020): Antigen-Specific Adaptive Immunity to SARS-CoV-2 in Acute COVID-19 and Associations with Age and Disease Severity. Cell 183: 996–1012 e1019.
Salzberger B, Buder F, Lampl B, Ehrenstein B, Hitzenbichler F, Hanses F (2020): Epidemiology of SARS-CoV-2 infection and COVID-19. Internist (Berl) 61: 782–788.
Schulte-Schrepping J, Reusch N, Paclik D, Bassler K, Schlickeiser S, Zhang B, Kramer B, Krammer T, Brumhard S, Bonaguro L et al. (2020): Severe COVID-19 Is Marked by a Dysregulated Myeloid Cell Compartment. Cell 182: 1419–1440.e23.
Seow J, Graham C, Merrick B, Acors S, Pickering S, Steel KJA, Hemmings O, O’Byrne A, Kouphou N, Galao RP, Betancor G, Wilson HD, Signell AW, Winstone H, Kerridge C, Huettner I, Jimenez-Guardeno JM, Lista MJ, Temperton N, Snell LB, Bisnauthsing K, Moore A, Green A, Martinez L, Stokes B, Honey J, Izquierdo-Barras A, Arbane G, Patel A, Tan MKI, O’Connell L, O’Hara G, MacMahon E, Douthwaite S, Nebbia G, Batra R, Martinez-Nunez R, Shankar-Hari M, Edgeworth JD, Neil SJD, Malim MH, Doores KJ (2020): Longitudinal observation and decline of neutralizing antibody responses in the three months following SARS-CoV-2 infection in humans. Nat Microbiol 5: 1598–1607.
Severe Covid GG, Ellinghaus D, Degenhardt F, Bujanda L, Buti M, Albillos A, Invernizzi P, Fernandez J, Prati D, Baselli G et al. (2020): Genomewide Association Study of Severe Covid-19 with Respiratory Failure. N Engl J Med 383: 1522–1534.
Shang J, Wan Y, Luo C, Ye G, Geng Q, Auerbach A, Li F (2020): Cell entry mechanisms of SARS-CoV-2. Proc Natl Acad Sci U S A 117: 11727–11734.
Sheahan TP, Sims AC, Zhou S, Graham RL, Pruijssers AJ, Agostini ML, Leist SR, Schafer A, Dinnon KH 3rd, Stevens LJ, Chappell JD, Lu X, Hughes TM, George AS, Hill CS, Montgomery SA, Brown AJ, Bluemling GR, Natchus MG, Saindane M, Kolykhalov AA, Painter G, Harcourt J, Tamin A, Thornburg NJ, Swanstrom R, Denison MR, Baric RS (2020): An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice. Sci Transl Med 12(541): eabb5883.
Shi J, Wen Z, Zhong G, Yang H, Wang C, Huang B, Liu R, He X, Shuai L, Sun Z, Zhao Y, Liu P, Liang L, Cui P, Wang J, Zhang X, Guan Y, Tan W, Wu G, Chen H, Bu Z (2020): Susceptibility of ferrets, cats, dogs, and other domesticated animals to SARS-coronavirus 2. Science 368(6494): 1016–1020.
Shilts J. Crozier TWM, Greenwood EJD, Lehner PJ, Wright GJ (2020): No evidence for basigin/CD147 as a direct SARS-CoV-2 spike binding receptor. Sci Rep 11: 413.
Silvin A, Chapuis N, Dunsmore G, Goubet AG, Dubuisson A, Derosa L, Almire C, Henon C, Kosmider O, Droin N, Rameau P, Catelain C, Alfaro A, Dussiau C, Friedrich C, Sourdeau E, Marin N, Szwebel TA, Cantin D, Mouthon L, Borderie D, Deloger M, Bredel D, Mouraud S, Drubay D, Andrieu M, Lhonneur AS, Saada V, Stoclin A, Willekens C, Pommeret F, Griscelli F, Ng LG, Zhang Z, Bost P, Amit I, Barlesi F, Marabelle A, Pene F, Gachot B, Andre F, Zitvogel L, Ginhoux F, Fontenay M, Solary E (2020): Elevated Calprotectin and Abnormal Myeloid Cell Subsets Discriminate Severe from Mild COVID-19. Cell 182(6): 1401–1418.e18.
Simonovich VA, Burgos Pratx LD, Scibona P, Beruto MV, Vallone MG, Vazquez C, Savoy N, Giunta DH, Perez LG, Sanchez MDL, Gamarnik AV, Ojeda DS, Santoro DM, Camino PJ, Antelo S, Rainero K, Vidiella GP, Miyazaki EA, Cornistein W, Trabadelo OA, Ross FM, Spotti M, Funtowicz G, Scordo WE, Losso MH, Ferniot I, Pardo PE, Rodriguez E, Rucci P, Pasquali J, Fuentes NA, Esperatti M, Speroni GA, Nannini EC, Matteaccio A, Michelangelo HG, Follmann D, Lane HC, Belloso WH, PlasmAr Study Group (2020): A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia. N Engl J Med 384(7): 619–629.
Sit THC, Brackman CJ, Ip SM, Tam KWS, Law PYT, To EMW, Yu VYT, Sims LD, Tsang DNC, Chu DKW, Perera RAPM, Poon LLM, Peiris M (2020): Infection of dogs with SARS-CoV-2. Nature 586(7831).
Sokal A, Chappert P, Roeser A, Barba-Spaeth G, Fourati S, Azzaoui I, Vandenberghe A, Fernandez I, Bouvier-Alias M, Crickx E Beldi-Ferchiou a, Hue S, Languille L, Michel M, Baloul S, Noizat-Pirenne F, Luka M, Mahevas M (2021): Maturation and persistence of the anti-SARS-CoV-2 memory B cell response. Cell 184(5): 1201–1213.e14.
Stadlbauer D, Tan J, Jiang K, Hernandez MM, Fabre S, Amanat F, Teo C, Arunkumar GA, McMahon M, Capuano C, Twyman K, Jhang J, Nowak MD, Simon V, Sordillo EM, van Bakel H, Krammer F (2020): Repeated cross-sectional sero-monitoring of SARS-CoV-2 in New York City. Nature 590(7844): 146–150.
Sterlin D, Mathian A, Miyara M, Mohr A, Anna F, Claer L, Quentric P, Fadlallah J, Devilliers H, Ghillani P, Gunn C, Hockett R, Mudumba S, Guihot A, Luyt CE, Mayaux J, Beurton A, Fourati S, Bruel T, Schwartz O, Lacorte JM, Yssel H, Parizot C, Dorgham K, Charneau P, Amoura Z, Gorochov G (2020): IgA dominates the early neutralizing antibody response to SARS-CoV-2. Sci Transl Med 13(577): eabd2223.
Stratton CW, Tang YW, Lu H (2020): Pathogenesis-directed therapy of 2019 novel coronavirus disease. J Med Virol 93: 1320–1342.
Tay MZ, Poh CM, Renia L, MacAry PA, Ng LFP (2020): The trinity of COVID-19: immunity, inflammation and intervention. Nat Rev Immunol 20: 363–374.
Tobin MJ, Laghi F, Jubran A (2020): Why COVID-19 Silent Hypoxemia Is Baffling to Physicians. Am J Respir Crit Care Med 202: 356–360.
Trump S, Lukassen S, Anker MS, Chua RL, Liebig J, Thurmann L, Corman VM, Binder M, Loske J, Klasa C, Krieger T, Hennig BP, Messingschlager M, Pott F, Kazmierski J, Twardziok S, Albrecht JP, Eils J, Hadzibegovic S, Lena A, Heidecker B, Bürgel T, Steinfeldt J, Goffinet C, Kurth F, Witzenrath M, Völker MT, Müller SD, Liebert UG, Ishaque N, Kaderali L, Sander LE, Drosten C, Laudi S, Eils R, Conrad C, Landmesser U, Lehmann I (2020): Hypertension delays viral clearance and exacerbates airway hyperinflammation in patients with COVID-19. Nat Biotechnol: DOI 10.1038/s41587-020-00796-1.
V’Kovski P, Kratzel A, Steiner S, Stalder H, Thiel V (2020): Coronavirus biology and replication: implications for SARS-CoV-2. Nat Rev Microbiol 19: 155–170.
van Doremalen N, Bushmaker T, Morris DH, Holbrook MG, Gamble A, Williamson BN, Tamin A, Harcourt JL, Thornburg NJ, Gerber SI, Lloyd-Smith JO, de Wit E, Munster VJ (2020): Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1. N Engl J Med 382(16): 1564–1567.
Verano-Braga T, Martins ALV, Motta-Santos D, Campagnole-Santos MJ, Santos RAS (2020): ACE2 in the renin–angiotensin system. Clin Sci 134: 3063–3078.
Voysey M, Clemens SAC, Madhi SA, Weckx LY, Folegatti PM, Aley P., Angus B, Baillie VL, Barnabas SL, Bhorat QE et al. (2020): Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet 397(10269): 99–111.
Wajnberg A, Amanat F, Firpo A, Altman DR, Bailey MJ, Mansour M, McMahon M, Meade P, Mendu DR, Muellers K, Stadlbauer D, Stone K, Strohmeier S, Simon V, Aberg J, Reich DL, Krammer F, Cordon-Cardo C (2020): Robust neutralizing antibodies to SARS-CoV-2 infection persist for months. Science 370(6521): 1227–1230.
Walsh KA, Jordan K, Clyne B, Rohde D, Drummond L, Byrne P, Ahern S, Carty PG, O’Brien KK, O’Murchu E, O’Neill M, Smith SM, Ryan M, Harrington P (2020): SARS-CoV-2 detection, viral load and infectivity over the course of an infection. J Infect 81(3): 357–371.
Wang K, Chen W, Zhou YS, Lian JQ, Zhang Z, Du P, Gong L, Zhang Y, Cui HY, Geng JJ Wang B, Sun XX, Wang CF, Yang X, Lin P, Deng YQ, Wei D, Yang XM, Zhu YM, Zhang K, Zheng ZH, Miao JL, Guo, T, Shi Y, Zhang J, Fu L, Wang QY, Bian H, Zhu P, Chen ZN (2020a): SARS-CoV-2 invades host cells via a novel route: CD147-spike protein. bioRxiv: DOI 10.1101/2020.03.14.988345 (preprint).
Wang Q, Jiang H, Xie Y, Zhang T, Liu S, Wu S, Sun Q, Song S Wang W, Deng X, Ren L, Qin T, Horby P, Uyeki T, Yu H (2020b): Long-term clinical prognosis of human infections with avian influenza A(H7N9) viruses in China after hospitalization. EClinicalMedicine 20: 100282.
Weinreich DM, Sivapalasingam S, Norton T, Ali S, Gao H, Bhore R, Musser BJ, Soo Y, Rofail D, Im J, Perry C, Pan C, Hosain R, Mahmood A, Davis JD, Turner KC, Hooper AT, Hamilton JD, Baum A, Kyratsous CA, Kim Y, Cook A, Kampman W, Kohli A, Sachdeva Y, Graber X, Kowal B, DiCioccio T, Stahl N, Lipsich L, Braunstein N, Herman G, Yancopoulos GD (2020): REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19. N Engl J Med 384: 238–251.
Williamson EJ, Walker AJ, Bhaskaran K, Bacon S, Bates C, Morton CE, Curtis HJ, Mehrkar A, Evans D. Inglesby P, Cockburn J, McDonald HI, MacKenna B, Tomlinson L, Douglas IJ, Rentsch CT, Mathur R, Wong AYS, Grieve R, Harrison D, Forbes H, Schultze A, Croker R, Parry J, Hester F, Harper S, Perera R, Evans SJW, Smeeth L, Goldacre B (2020): Factors associated with COVID-19-related death using OpenSAFELY. Nature 584(7821): 430–436.
Wolfel R, Corman VM, Guggemos W, Seilmaier M, Zange S, Muller MA, Niemeyer D, Jones TC, Vollmar P, Rothe C, Hoelscher M, Bleicker T, Brünink S, Schneider J, Ehmann R, Zwirglmaier K, Drosten C, Wendtner C (2020): Virological assessment of hospitalized patients with COVID-2019. Nature 581: 465–469.
World Health Organization (2020a): Middle East respiratory syndrome. http://www.emro.who.int/health-topics/mers-cov/mers-outbreaks.html (accessed 22.03.2021).
World Health Organization (2020b): Novel Coronavirus (2019-nCoV), Situation Report 1, 21 JANUARY 2020. https://www.who.int/docs/default-source/coronaviruse/situation-reports/… (accessed 22.03.2021).
World Health Organization (2020c): Pneumonia of unknown cause – China. https://www.who.int/csr/don/05-january-2020-pneumonia-of-unkown-cause-c… (accessed 22.03.2021).
World Health Organization (2021): Weekly epidemiological update – 1 December 2020. https://www.who.int/publications/m/item/weekly-epidemiological-update–16-march-2021 (accessed 16.03.2021).
Wyler E, Mösbauer K, Franke V, Diag A, Gottula Lina T, Arsie R, Klironomos F, Koppstein Honzke K, D, Ayoub S, Buccitelli C Hoffmann K, Richter A, Legnini I, Ivanov A, Tommaso M, Del Giudice S, Papies J, Praktiknjo S, Meyer TF, Müller MA, Niemeyer D, Hocke A, Selbach M, Akalin A, Rajewsky N, Drosten C, Landthaler M (2020): Transcriptomic profiling of SARS-CoV-2 infected human cell lines identifies HSP90 as target for COVID-19 therapy. iScience 24(3): 102151.
Wyllie AL, Fournier J, Casanovas-Massana A, Campbell M, Tokuyama M, Vijayakumar P, Warren JL, Geng B, Muenker MC, Moore AJ.et al. (2020): Saliva or Nasopharyngeal Swab Specimens for Detection of SARS-CoV-2. N Engl J Med 383(13): 1283–1286.
Yang L, Han Y, Nilsson-Payant BE, Gupta V, Wang P, Duan X, Tang X, Zhu J, Zhao Z, Jaffre F, Zhang T, Kim TW, Harschnitz O, Redmond D, Houghton S, Liu C, Naji A, Ciceri G, Guttikonda S, Bram Y, Nguyen DHT, Cioffi M, Chandar V, Hoagland DA, Huang Y, Xiang J, Wang H, Lyden D, Borczuk A, Chen HJ, Studer L, Pan FC, Ho DD, tenOever BR, Evans T, Schwartz RE, Chen S (2020a): A Human Pluripotent Stem Cell-based Platform to Study SARS-CoV-2 Tropism and Model Virus Infection in Human Cells and Organoids. Cell Stem Cell 27(1): 125–136.e7.
Yang L, Liu S, Liu J, Zhang Z, Wan X, Huang B, Chen Y, Zhang Y (2020b): COVID-19: immunopathogenesis and Immunotherapeutics. Signal Transduct Target Ther 5: 128.
Yurkovetskiy L, Wang X, Pascal KE, Tomkins-Tinch C, Nyalile TP, Wang Y, Baum A, Diehl WE, Dauphin A, Carbone C, Veinotte K, Egri SB, Schaffner SF, Lemieux JE, Munro JB, Rafique A, Barve A, Sabeti PC, Kyratsous CA, Dudkina NV, Shen K, Luban J (2020): Structural and Functional Analysis of the D614G SARS-CoV-2 Spike Protein Variant. Cell 183(3): 739–751.e8.
Zhang B, Zhou X, Qiu Y, Song Y, Feng F, Feng J, Song Q, Jia Q, Wang J (2020a): Clinical characteristics of 82 cases of death from COVID-19. PLoS One 15: e0235458.
Zhang Q, Bastard P, Liu Z, Le Pen J, Moncada-Velez M, Chen J, Ogishi M, Sabli IKD, Hodeib S, Korol C et al. (2020b): Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science 370(6515): eabd4570.
Zhong P, Xu J, Yang D, Shen Y, Wang L, Feng Y, Du C, Song Y, Wu C, Hu X, Sun Y (2020): COVID-19-associated gastrointestinal and liver injury: clinical features and potential mechanisms. Signal Transduct Target Ther 5: 256.
Zhu FC, Li YH, Guan XH, Hou LH, Wang WJ, Li JX, Wu SP, Wang BS, Wang Z, Wang L, Jia SY, Jiang HD, Wang L, Jiang T, Hu Y, Gou JB, Xu SB, Xu JJ, Wang XW, Wang W, Chen W (2020): Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial. Lancet 395(10240): 1845–1854.
Ziegler CGK, Allon SJ, Nyquist SK, Mbano IM, Miao VN, Tzouanas, CN, Cao Y, Yousif AS, Bals J, Hauser BM et al. (2020): SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues. Cell 181(5): 1016–1035.
Zohar T, Loos C, Fischinger S, Atyeo C, Wang C, Slein MD, Burke J, Yu J, Feldman J, Hauser BM, Caradonna T, Schmidt AG, Cai Y, Streeck H, Ryan ET, Barouch DH, Charles RC, Lauffenburger DA, Alter G (2020): Compromised Humoral Functional Evolution Tracks with SARS-CoV-2 Mortality. Cell 183(6): 1508–1519.e12.
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